PROJECT SUMMARY: We previously demonstrated in mice that the major pathogenic features (eosinophilic airway inflammation and airway hyperresponsiveness [AHR]) were markedly enhanced in mice exposed to repeated social stress and these changes were associated with impaired glucocorticoid receptor (GR) expression and function. In studies on non-human primates (rhesus macaques) at the California National Primate Research Center (CNPRC) at UC Davis, anxious temperament (an early manifestation of psychosocial stress) in young monkeys was significantly associated with AHR and glucocorticoid non-responsiveness of immune cells. We propose to investigate secoisolariciresinol diglucoside (SDG), a novel antiinflammatory molecule, and natural non-toxic bioactive component of flaxseed, as an alternative/adjunct therapy for glucocorticoid resistant asthma. SDG has proven reducing, chelating and free radical scavenging activities in vitro and in vivo and it induces activation of nuclear factor erythroid 2-related factor 2 (NRF2) a major anti-oxidant transcription regulator and inhibitor of NF-kB. Our aim 1 is to evaluate the effects of the synthetic version of SDG (LGM2605) on airway hyperresponsiveness (AHR), inflammatory markers of blood and bronchoalveolar lavage (BAL) immune cells and glucocorticoid function of peripheral blood mononuclear cells of socially stressed rhesus macaques. Aim 2 is to assess LGM2605 treatment on genetic and epigenetic regulation of the GR, NF-kB and NRF2 using bronchial brush biopsies. The strength and novelty of our proposal is the unique Rhesus macaque model system of asthma associated with psychosocial stress and glucocorticoid resistance, and the synthetic availability of LGM2605 through LignaMed. Upon completion, these studies will lay the groundwork for subsequent Phase II trial and ultimately to human clinical projects.